Effects of Renal Disease in the Management of Diabetics

CARLOS R. HAMILTON, JR., MD, FACE: Hello, I'm Dr. Carlos Hamilton, welcome to the AACE Clinical Conversations. In this program, we will discuss the effects of renal disease in the management of diabetics.

Joining me today to discuss this topic are Dr. Joseph Torre, Senior Endocrinologist at the Buffalo Medical Group and Assistant Clinical Professor at the State University of New York in Buffalo. And also with us is Dr. Addison Taylor, Professor of Medicine and Chief of the Hypertension and Clinical Pharmacology Section in the Department of Medicine at the Baylor College of Medicine in Houston. Thank you both for being with us today.

Dr. Torre, what is your understanding of the effects of cardiovascular disease and diabetics [sic] in patients with chronic kidney disease? Or on the mortality of these patients?

JOSEPH J. TORRE, MD, FACP, FACE: Carlos, this is a very important issue for our endocrine colleagues and our primary care colleagues. Certainly the major cause of death with chronic kidney disease is cardiovascular disease. 50% of patients with end-stage renal disease have diabetes and a great majority have either diabetes, hypertension or both.

There are many causes for cardiovascular disease with chronic kidney disease beginning with the initial microangiopathy that starts the nephropathy and progressing to the left ventricular dysfunction and macrovascular disease that usually results from activation of the -- hyper-activation of the sympathetic nervous system, the renin angiotensin-aldosterone system.

CARLOS R. HAMILTON, JR., MD, FACE: Dr. Taylor, would you agree that cardiovascular disease represents a greater threat to patients with stage III and stage IV kidney disease than does actual progression to dialysis or end-stage kidney disease?

ADDISON TAYLOR, MD, PhD: Very definitely. Not only do patients have a higher incidence, but addressing the problems associated with diabetes and hypertension in our patients with CKD actually has a greater impact on their mortality.

CARLOS R. HAMILTON, JR., MD, FACE: Dr. Taylor, how important is blood pressure control in the renal-protection aspect of our care of patients with diabetes?

ADDISON TAYLOR, MD, PhD: Blood pressure control is perhaps of paramount importance. A number of studies, including the UKPDS study, suggested that tight blood pressure control, defined in that study as blood pressures less than 140 over 90, in fact conferred significant protection against cardiovascular events. And there are additional data to suggest that, the lower the blood pressure, the better and it may actually trump both lipids and glucose control in terms of its importance to the overall well-being of the diabetic.

CARLOS R. HAMILTON, JR., MD, FACE: I recall, in that study, that what seemed to me to be rather trivial degrees of lowering of blood pressure, especially diastolic blood pressure, contributed very significantly to the better outcomes in the patients. What level of blood pressure should a clinician seek to obtain in these patients?

ADDISON TAYLOR, MD, PhD: That's a somewhat controversial topic. There are a number of studies that have attempted to achieve blood pressures of, frequently, less than 130 systolic and 80 diastolic. Very few of them have actually succeeded in doing that and the UKPDS study to which you referred actually was able to lower the blood pressure approximately 10 mm of mercury systolic and 5 diastolic, but still only to levels above 140. So getting to that 130 goal is frequently very challenging.

In general, I think if you get to the systolic goal, that you've elected -- you and the patient have to, obviously, do this together, you're likely to achieve good diastolic blood pressure control. If you focus on the diastolic blood pressure, you may or may not get to the systolic value that you're shooting for.

CARLOS R. HAMILTON, JR., MD, FACE: So, Joe, how does the presence of chronic kidney disease affect your management of patients with diabetes?

JOSEPH J. TORRE, MD, FACP, FACE: Carlos, I look at it much like I look at patients with prediabetes. We're always looking for ways to prevent the progression of an illness. And I look at all diabetic patients as having pre-chronic kidney disease. And, that is, I try to use agents that are going to benefit kidney function or -- and certainly not hurt it.

CARLOS R. HAMILTON, JR., MD, FACE: Joe, do you use metformin in patients with chronic kidney disease in the control of their blood sugar?

JOSEPH J. TORRE, MD, FACP, FACE: Yes, I do. I think that, while there's no diabetic agents that clearly cause any deterioration in renal function, there are certain ones that, like metformin, that one has to res- -- curtail their usage once renal function has deteriorated. What that point is is not perfectly clear with metformin. I'd say GFR's over 50 cc’s per minute certainly seem reasonable to continue using metformin.

CARLOS R. HAMILTON, JR., MD, FACE: Do you tend to use other drugs in association with metformin, such as the sulfonylureas or --?

JOSEPH J. TORRE, MD, FACP, FACE: The first-generation sulfonylureas generally were longer-acting and also would have to be curtailed to prevent hypoglycemia.

CARLOS R. HAMILTON, JR., MD, FACE: So the shorter-acting sulfonylureas and lower doses of metformin can be successfully used in patients that have some degree of impairment of kidney function. Is that a fair statement?

JOSEPH J. TORRE, MD, FACP, FACE: Yes.

CARLOS R. HAMILTON, JR., MD, FACE: Addison, what are the factors in vascular disease in patients with diabetes that tend to affect their cardiovascular mortality?

ADDISON TAYLOR, MD, PhD: Well, that question has perhaps a long and somewhat complicated answer.

So there is this inflammatory cascade that starts off with reactive oxygen, which is made in much higher concentrations in diabetics than it is in nondiabetics. That's exaggerated even more in hypertensives and it induces this entire cascade of inflammatory responses.

CARLOS R. HAMILTON, JR., MD, FACE: So the combination of diabetes and hypertension leads to factors including these that affect endothelial dysfunction and that, in turn, leads to the progression of kidney disease and generalized vascular disease that it's so common in these patients. Is that right?

ADDISON TAYLOR, MD, PhD: That is absolutely correct.

CARLOS R. HAMILTON, JR., MD, FACE: Joe, what is your feeling about the blood pressure goals that you would cite -- try to obtain in patients with diabetes and with chronic kidney disease? And what would be your initial choice of therapy in this decision?

JOSEPH J. TORRE, MD, FACP, FACE: Well, while 130 over 80 has become the target for treatment of hypertension in diabetes, if there is significant proteinuria or chronic kidney disease evident, that goal is -- the target is generally lowered to 125 over 75. Now, how hard and fast that is, is certainly open to question.

We've -- Dr. Taylor has mentioned that, from various studies, it would appear that potentially even lower blood pressures than that may be favorable.

The UKPDS itself, patients who are over 125 to 149, I believe, systolic, had a 1.5 greater incidence of cardiovascular events than patients who had systolic blood pressures under 125. Now, that, of course, is epidemiologic and does not necessarily mean that treatment to those levels would be helpful.

CARLOS R. HAMILTON, JR., MD, FACE: Now, what I understand you saying is that the lower the blood pressure --

JOSEPH J. TORRE, MD, FACP, FACE: Potentially.

CARLOS R. HAMILTON, JR., MD, FACE: -- it is potentially better for the patient in terms of their kidney effects and their vascular effects, as long as, of course, that they're not having significant symptomatic orthostatic hypotension. Is that a fair statement?

JOSEPH J. TORRE, MD, FACP, FACE: I believe so.

CARLOS R. HAMILTON, JR., MD, FACE: What do -- do you use certain drugs initially in diabetic patients as opposed to, say, other patients with hypertension?

JOSEPH J. TORRE, MD, FACP, FACE: We always start with -- if possible, with a angiotensin-converting enzyme or an angiotensin-receptor blocker. If blood pressure is more than 20 points systolic or 10 points diastolic over the goal, so, therefore, about 130, 150 over 90, it's generally recommended to add a second agent with the ACE inhibitor, usually a diuretic. And we try to use always low-dose thiazide diuretics, not loop diuretics, and not high doses of thiazide diuretics.

CARLOS R. HAMILTON, JR., MD, FACE: I'm particularly happy to use these drugs in patients that have even very slight degrees of microalbuminuria. And now that we've gotten -- or at least I've gotten used to using the microalbumin creatinine ratio, instead of having to do a 24-hour collection, I do this on patients routinely. And, if their microalbumin is even slightly over 30, I will not hesitate to put them on an ACE inhibitor, even if their blood pressure is quite normal. Would you agree with that?

JOSEPH J. TORRE, MD, FACP, FACE: Yes, I do, I agree. And, unless there's significant hyperkalemia, there's probably no reason not to use an ACE inhibitor with chronic kidney disease.

CARLOS R. HAMILTON, JR., MD, FACE: Addison, how does the drug therapy of hypertension in diabetic patients differ, if it does, from the way you would treat other patients?

ADDISON TAYLOR, MD, PhD: Well, I think Dr. Torre has pointed out an important difference and that's that, even in individuals with normal blood pressures, if there is microalbuminuria, it's recommended to start either an ACE inhibitor or an ARB.

I'm not sure we know which of those is the best and there are some data to suggest that, perhaps, in certain patients, combinations of those two may actually have superior benefits on urinary protein excretion than one alone. There do not appear to be any substantive differences in the class of either ACE inhibitors or ARBs.

The question is: What else do you add at that point? And one of our clinical concerns is always not negating the benefit of an ACE or an ARB --

CARLOS R. HAMILTON, JR., MD, FACE: Yeah, very good point.

ADDISON TAYLOR, MD, PhD: -- and so I think we can derive some satisfaction from several studies that would suggest combinations of calcium channel blockers with ACEs or ARBs, in fact, don't lose the antiproteinuric benefits of the ACE or the ARB.

Part of that may be better blood pressure control. I think, without good blood pressure control in the hypertensive diabetic, you're kind of -- the tail is wagging the dog. You actually need to have some degree of good blood pressure control and then you can optimize therapy to reduce some of these other target organ -- end-organ effects that we see in diabetics.

CARLOS R. HAMILTON, JR., MD, FACE: One of the issues that occasionally is brought up is the importance, perhaps, of monitoring the creatinine in patients that are being treated with ACE inhibitors or ARBs. Do these drugs significantly affect creatinine levels and at what point should that be of great concern to us?

ADDISON TAYLOR, MD, PhD: Well, I had a clinical professor of nephrology say to me, "If you start a patient on an ACE or an ARB and you don't get some increase in creatinine, you're probably not giving enough ACE or ARB." So I think we would anticipate initial responses to therapy will be associated with very modest increases in creatinine.

Some people have recommended that values increased 40% above a baseline value would be acceptable, but, beyond that, you have to worry about things like bilateral renal artery stenosis as a potential contributor.

The long-term benefits, though, are to actually reduce the creatinine as you get healing of the microangiopathy --

CARLOS R. HAMILTON, JR., MD, FACE: Well, that's good to hear you say that --

ADDISON TAYLOR, MD, PhD: -- in the kidney, etc.

CARLOS R. HAMILTON, JR., MD, FACE: Addison, we've already mentioned the fact that using multiple drugs in patients with diabetes and kidney disease is often what is necessary to achieve the degree of control. Are there certain drugs that you tend to shy away from or to not use in these patients?

ADDISON TAYLOR, MD, PhD: Using drugs as single therapy that have significant adverse metabolic consequences are drugs that I tend not to use alone.

Either fortunately or unfortunately, in most diabetics, we end up needing multiple drugs in most patients. Studies like IDNT and RENAL were using up to four drugs to achieve good blood pressure control. And, clearly, there was still benefit associated with the ARB in each of those studies and other cardiovascular benefits as well.

So I tend to use more drugs but at lower doses and try to achieve drugs that complement one another.

CARLOS R. HAMILTON, JR., MD, FACE: I'm glad to hear you say that, because I have felt, for some time, that using multiple drugs at lower levels is better for the -- not only for the control, but for the presence of side effects than it is to use maximum doses of a smaller number of drugs and that seems to be what you would agree with.

ADDISON TAYLOR, MD, PhD: Yes.

CARLOS R. HAMILTON, JR., MD, FACE: Dr. Torre, how do you feel about that? Are there certain drugs that you tend to shy away from? What about beta blockers in patients with diabetes?

JOSEPH J. TORRE, MD, FACP, FACE: Yeah, I think second- and third-line agents should include beta blockers, particularly alpha beta blockers such as carvedilol or selective beta blockers such as nebivolol, which will be released soon.

CARLOS R. HAMILTON, JR., MD, FACE: And, of course, there is evidence that this benefits patients that have preexisting ischemic heart disease, too, so there's some benefit.

JOSEPH J. TORRE, MD, FACP, FACE: Yes. Many of our patients need it and inside [sic] -- and instead of increasing insulin resistance, as most beta blockers do, these agents improve insulin sensitivity.

Calcium channel blockers also certainly are commonly used in combination and should be used, preferably the nondihydropyridine calcium channel blockers, which have been shown to decrease microalbuminuria, if possible.

CARLOS R. HAMILTON, JR., MD, FACE: Well, thank you very much. I think this has been a very helpful discussion of a very important issue for our patients with diabetes. And I appreciate your being here.

Again, thank you very much for listening and I'm Dr. Carlos Hamilton.